Amygdaloid neurocircuits integrate neuroendocrine responses to stress. Accordingly, individuals with stress-related affective disorders, such as depression, show enhanced activation of the amygdala in combination with hypothalamo-pituitary-adrenocortical dysfunction. Both amygdaloid hyperactivity and adrenocortical dysfunction resolve with antidepressant treatment, suggesting a connection between the two. This competing renewal is thus designed to assess amygdaloid mechanisms of stress regulation. Previous work on amygdaloid neuroendocrine interactions strongly implicates the medial amygdaloid nucleus as a focus of depression-related dysfunction. This nucleus is known to project heavily to hypothalamic relay neurons regulating pituitary-adrenal stimulatory functions of the hypothalamic paraventricular nucleus, and is implicated in control of stress responsiveness, sexual behavior and aggression. Like all amygdaloid nuclei, paraventricular projections of the medial nucleus are sparse, making it likely that interactions are indirect. In combination with the extensive GABAergic phenotype of both the medial amygdala and its primary paraventricular nucleus-projecting targets, we hypothesize that the medial amygdala activates the hypothalamo-pituitary-adrenocortical axis by trans-synaptic disinhibition, using GABA-GABA connections in the bed nucleus of the stria terminalis and preoptic area. Four Specific Aims are proposed to: 1) elucidate the neuroanatomical organization of medial amygdala-paraventricular connections, 2) demonstrate the importance of medial amygdaloid GABA pathways in stress regulation, 3) identify GABAergic mechanisms responsible for amygdaloid disinhibition of the hypothalamo-pituitary-adrenocortical axis, and 4) establish a role for the medial amygdala in chronic stress-induced HPA dysfunction. These studies are expected to identify a specific role for the medial amygala in driving stress responses, and establish the primacy of GABAergic neurocircuits in abnormal stress axis function seen in depression and other affective disease states.